The present invention relates to methods and compounds for the treatment of HIV infection. The disease Acquired Immunodeficiency Syndrome (AIDS) is the end result of infection by the distinct retroviruses, human immunodeficiency virus type-1 (HIV-1) or type-2 (HIV-2). Several critical points in the virus life cycle have been identified as possible targets for therapeutic intervention. Inhibition of one of these, the transcription of viral RNA to viral DNA (reverse transcriptase, RT), has provided a number of the current therapies used in treating AIDS. Inhibition of reverse transcriptase provided the first form of treatment for HIV infection with 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT). Since then several inhibitors have been launched, broadly forming two classes: nucleoside analogues and non-nucleosides. As an example of the latter it has been found that certain benzoxazinones, e.g. efavirenz are useful in the inhibition of HIV RT. However, development of strains of the virus resistant to current RT inhibitors is a constant problem. Therefore, development of compounds effective against resistant strains is an important goal.
Pyrazole derivatives have been described in the literature with different uses (e.g. agrochemistry or treatment of stress-relating illness).
EP 0 627 423 describes pyrazole derivatives and their use as agrohorticultural bactericides.
U.S. Pat. No. 6,005,109 describes pyrazole derivatives and their use in the treatment of stress-relating illness.
No pyrazole derivatives have yet been described in the literature for the treatment of diseases mediated by the human immunodeficiency virus (HIV).
The invention is concerned with novel and known pyrazole derivatives, a process for their manufacture, pharmaceutical compositions and the use of such compounds in medicine, especially in the treatment of viral diseases. In particular, the compounds are inhibitors of the human immunodeficiency virus reverse transcriptase enzyme which is involved in viral replication. Consequently the compounds of this invention may be advantageously used as therapeutic agents for the treatment of diseases mediated by the human immunodeficiency virus (HIV).
The present invention describes the use of compounds of formula I 
wherein
R1 is optionally substituted C1-12-alkyl, C3-8-cycloalkyl, acyl, C1-4-alkylsulfonyl, optionally substituted phenylsulfonyl, aryl, heterocyclyl or C1-4-alkyl substituted with optionally substituted phenyl;
R2 is aryl;
R3 is C1-12-alkyl or C1-4-alkoxy-C1-4-alkyl;
A is a group selected from CH2-(aryl-C1-4-alkylamino), CH2-(aryl-C1-4-alkoxy),
CH2-(heterocyclyl-C1-4-alkoxy), C1-4-alkyl substituted with aryl or with heterocyclyl; or
A is a group of formula CH2-U-heterocyclyl,
wherein U is O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl; or
A is a group of formula CH(V)Z,
wherein V is OH or F, and
wherein Z is aryl or heterocyclyl; or
A is a group of formula CHxe2x95x90CHW,
wherein W is aryl or heterocyclyl;
X represents S or O;
for the treatment of diseases mediated by the human immunodeficiency virus (HIV) or for the preparation of a medicament for such treatment.
The term xe2x80x9calkylxe2x80x9d as used herein denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl including their different isomers. Preferably, xe2x80x9calkylxe2x80x9d optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7 or 1 to 6 carbon atoms. Most preferred, xe2x80x9calkylxe2x80x9d denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms.
Suitable substituents for the alkyl chain can be selected from one or more of aryl, heterocyclyl, alkoxy, hydroxy or halogen. The terms xe2x80x9carylxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d and xe2x80x9chalogenxe2x80x9d are defined below. Preferred substituents for the alkyl chain are 1-5 substituents selected from fluorine, chlorine and bromine, more preferred 1-5 fluorine substituents and most preferred 1-3 fluorine substituents.
In case more than one substituent is attached to the alkyl group, these substituents can be identical or different from each other.
Aryl (defined below) as substituent for the alkyl group can also be substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine. More preferred, the aryl is substituted with 1-3 substituents selected from methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine.
Heterocyclyl (defined below) as substituent for the alkyl group can also be substituted with 1, 2, 3 or 4 (where chemically possible) substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine. More preferred, the heterocyclyl is substituted with 1-2 substituents selected from methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine.
Alkyl in R1 is preferably an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7, 1 to 6 or 1 to 4 carbon atoms as defined above. Suitable substituents for the alkyl group are selected from aryl, heterocyclyl or halogen. Preferred substituents for the alkyl chain are 1-5 substituents selected from fluorine, chlorine and bromine, more preferred 1-5 fluorine substituents and most preferred 1-3 fluorine substituents. More preferred alkyl in R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl including their different isomers, trifluoromethyl or 2,2,2-trifluoro-ethyl. Most preferred alkyl in R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl.
Alkyl in R3 is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms and most preferred methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl including their different isomers. More preferred alkyl in R3 is an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein denotes an optionally substituted cycloalkyl group containing 3 to 8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which can also be fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle, e.g. to phenyl.
Suitable substituents for cycloalkyl can be selected from one or more of those named for alkyl.
Cycloalkyl in R1 is as defined above, preferably an unsubstituted cycloalkyl group containing 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. More preferred cycloalkyl in R1 is cyclopentyl or cyclohexyl.
The term xe2x80x9calkoxyxe2x80x9d as used herein denotes an optionally substituted straight or branched chain alkyl-oxy group containing 1 to 7 carbon atoms wherein the xe2x80x9calkylxe2x80x9d portion is as defined above. Examples for alkoxy groups are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, 1-sec-butyloxy, iso-butyloxy, tert.-butyloxy, pentyloxy, hexyloxy, heptyloxy including their different isomers.
Suitable substituents for the alkoxy group are selected from aryl, hydroxy, halogen or amino.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein denotes an alkoxy group containing 1 to 4 carbon atoms as defined above which is bonded to an alkyl group containing 1 to 4 carbon atoms (preferably 1-2 carbon atoms) as defined above. Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, tert.-butyloxybutyl including their different isomers. Preferred alkoxyalkyl group within the invention is C1-2-alkoxy-C1-2-alkyl.
Alkoxyalkyl in R3 is preferably methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl.
The term xe2x80x9cacylxe2x80x9d as used herein denotes a group of formula C(xe2x95x90O)H, C(xe2x95x90O)alkyl or C(xe2x95x90O)phenyl wherein alkyl is an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms. Most preferred acyl groups are C(xe2x95x90O)H, C(xe2x95x90O)alkyl or C(xe2x95x90O)phenyl wherein alkyl is an unsubstituted straight chain or branched hydrocarbon residue containing 1 to 4 carbon atoms.
Acyl inR1 is independently of each other preferably methylcarbonyl (acetyl), ethylcarbonyl (propionyl), propylcarbonyl, butylcarbonyl or phenylcarbonyl (benzoyl).
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein denotes a group of formula S(xe2x95x90O)2(alkyl) wherein the alkyl is an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms, preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms. More preferred alkylsulfonyl groups are methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, 1-sec-butylsulfonyl, iso-butylsulfonyl or tert.-butylsulfonyl. Alkylsulfonyl inR1 ispreferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, 1-sec-butylsulfonyl, iso-butylsulfonyl or tert.-butylsulfonyl.
The term xe2x80x9carylxe2x80x9d as used herein denotes an optionally substituted phenyl and naphthyl, both optionally benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle e.g. to cyclohexyl or cyclopentyl. Suitable substituents for aryl can be selected from 1, 2, 3, 4 or 5, preferably 1, 2 or 3 residues of those named for alkyl, preferably selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, nitro, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl. The substituents for aryl can also be selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine. In case more than one substituent is attached to the aryl group, these substituents can be identical or different from each other.
Aryl in R1 ispreferably phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 1-fluoro-phenyl, 2-fluoro-phenyl or 3-fluoro-phenyl. Most preferred aryl in R1 is phenyl.
Aryl in R2 is preferably phenyl or naphthyl.
xe2x80x9cOptionally substituted phenylxe2x80x9d as used herein includes phenyl substituted with 1-5 substituents, preferably 1, 2 or 3 residues of those selected C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano and nitro. The substituents for phenyl in
Rxe2x80x2 may also be selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine. Examples for the optionally substituted phenyl are phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 3,6-dimethylphenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,6-dimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,6-dihydroxyphenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,3,4,5,6-pentafluorophenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4-trichlorophenyl, 3,4,5-trichlorophenyl, 2,3,4,5,6-pentachlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 3,6-dibromophenyl, 2-cyano-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 2,3-dicyanophenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 3,4-dicyanophenyl, 3,5-dicyanophenyl, 3,6-dicyanophenyl, 2-nitro-phenyl, 3-nitro-phenyl, 4-nitro-phenyl, 2,3-dinitrophenyl, 2,4-dinitrophenyl, 2,5-dinitrophenyl, 2,6-dinitrophenyl, 3,4-dinitrophenyl, 3,5-dinitrophenyl, 3,6-dinitrophenyl, 1-chloro-2-methoxy-phenyl, 1-chloro-3-methoxy-phenyl, 1-chloro-4-methoxy-phenyl, 1-chloro-5-methoxy-phenyl, 2-chloro-1-methoxy-phenyl, 2-chloro-3-methoxy-phenyl, 2-chloro-4-methoxy-phenyl, 2-chloro-5-methoxy-phenyl, 3-chloro-1-methoxy-phenyl, 3-chloro-2-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 3-chloro-5-methoxy-phenyl. More preferred examples for the optionally substituted phenyl are phenyl, 2-methoxy-phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3,4-trichlorophenyl, 3,4,5-trichlorophenyl or 2,3,4,5,6-pentachlorophenyl. Most preferred examples for the optionally substituted phenyl are phenyl, 4-methoxy-phenyl, 3-chloro-phenyl or 3,5-dichlorophenyl.
The term xe2x80x9coptionally substituted phenylsulfonylxe2x80x9d as used herein denotes a group of formula S(xe2x95x90O)2(phenyl) wherein phenyl is optionally substituted with 1-5 substituents, preferably 1, 2 or 3 residues of those selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine. Examples for the optionally substituted phenyl are as mentioned above, preferably phenylsulfonyl.
The term xe2x80x9cC1-4-alkyl substituted with arylxe2x80x9d as used herein denotes a C1-4-alkyl as defined above which is substituted with an aryl group (preferably a phenyl group) or preferably a substituted aryl group (preferably a substituted phenyl group) which is substituted with 1, 2, 3, 4 or 5, preferably 1, 2 or 3 residues of those substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl. The substituents for substituted aryl (preferably phenyl) may also be selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine and cyano, or the substituents may optionally be selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine. In case more than one substituent is attached to the aryl group (preferably phenyl group), these substituents can be identical or different from each other. Preferred substituents for the substituted aryl (preferably phenyl) are selected from methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine or the substituents are selected from methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine, bromine, cyano, amino, methyl-amino and di-methyl-amino. Within the invention xe2x80x9cC1-2-alkyl substituted with optionally substituted phenylxe2x80x9d is preferred. Examples are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, tolylmethyl, tolylethyl, tolylpropyl, tolylbutyl, 2,3-dimethylphenylmethyl, 2,4-dimethylphenylmethyl, 2,5-dimethylphenylmethyl, 2,6-dimethylphenylmethyl, 3,4-dimethylphenylmethyl, 3,5-dimethylphenylmethyl, 3,6-dimethylphenylmethyl, methoxyphenylmethyl, methoxyphenylethyl, methoxyphenylpropyl, methoxyphenylbutyl, dimethoxyphenylmethyl, dimethoxyphenylethyl, dimethoxyphenylpropyl, dimethoxyphenylbutyl, 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 4-hydroxyphenylmethyl, 2,3-dihydroxyphenylmethyl, 2,4-dihydroxyphenylmethyl, 2,5-dihydroxyphenylmethyl, 2,6-dihydroxyphenylmethyl, 3,4-dihydroxyphenylmethyl, 3,5-dihydroxyphenylmethyl, 3,6-dihydroxyphenylmethyl, 2-hydroxyphenylethyl, 3-hydroxyphenylethyl, 4-hydroxyphenylethyl, 2-hydroxyphenylpropyl, 3-hydroxyphenylpropyl, 4-hydroxyphenylpropyl, 2-hydroxyphenylbutyl, 3-hydroxyphenylbutyl, 4-hydroxyphenylbutyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2,3-difluorophenylmethyl, 2,4-difluorophenylmethyl, 2,5-difluorophenylmethyl, 2,6-difluorophenylmethyl, 3,4-difluorophenylmethyl, 3,5-difluorophenylmethyl, 3,6-difluorophenylmethyl, 2-fluorophenylethyl, 3-fluorophenylethyl, 4-fluorophenylethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 2,3-dichlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,5-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 3,4-dichlorophenylmethyl, 3,5-dichlorophenylmethyl, 3,6-dichlorophenylmethyl, 2-chlorophenylethyl, 3-chlorophenylethyl, 4-chlorophenylethyl, 2-bromophenylmethyl, 3-bromophenylmethyl, 4-bromophenylmethyl, 2,3-dibromophenylmethyl, 2,4-dibromophenylmethyl, 2,5-dibromophenylmethyl, 2,6-dibromophenylmethyl, 3,4-dibromophenylmethyl, 3,5-dibromophenylmethyl, 3,6-dibromophenylmethyl, 2-bromophenylethyl, 3-bromophenylethyl, 4-bromophenylethyl, 2-cyanophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl, 2,3-dicyanophenylmethyl, 2,4-dicyanophenylmethyl, 2,5-dicyanophenylmethyl, 2,6-dicyanophenylmethyl, 3,4-dicyanophenylmethyl, 3,5-dicyanophenylmethyl, 3,6-dicyanophenylmethyl, 2-dimethylaminophenylmethyl, 3-dimethylaminophenylmethyl 4-dimethylaminophenylmethyl, 2,3-di-dimethylaminophenylmethyl, 2,4-di-dimethylaminophenylmethyl, 3,5-di-dimethylaminophenylmethyl, 2,6-di-dimethylaminophenylmethyl, 3,4-di-dimethylaminophenylmethyl, 3,5-di-dimethylaminophenylmethyl or 3,6-di-dimethylaminophenylmethyl.
C1-4-alkyl substituted with optionally substituted phenyl for R1 is as defined above, preferably phenylmethyl (benzyl).
C1-4-alkyl substituted with optionally substituted phenyl for the substituent A are as defined above, preferably phenylmethyl (benzyl), 4-methylphenylmethyl, 4-methoxyphenylmethyl, 4-nitrophenylmethyl, 4-fluorophenylmethyl, 4-chlorophenylmethyl, 4-bromophenylmethyl, phenylethyl, 4-methylphenylethyl, 4-methoxyphenylethyl, 4-nitrophenylethyl, 4-fluorophenylethyl, 4-chlorophenylethyl, 4-bromophenylethyl, phenylpropyl, phenylbutyl, 2-cyanophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl, 2,3-dicyanophenylmethyl, 2,4-dicyanophenylmethyl, 2,5-dicyanophenylmethyl, 2,6-dicyanophenylmethyl, 3,4-dicyanophenylmethyl, 3,5-dicyanophenylmethyl, 3,6-dicyanophenylmethyl, 2-dimethylaminophenylmethyl, 3-dimethylaminophenylmethyl, 4-dimethylaminophenylmethyl, 2,3-di-dimethylaminophenylmethyl, 2,4-di-dimethylaminophenylmethyl, 2,5-di-dimethylaminophenylmethyl, 2,6-di-dimethylaminophenylmethyl, 3,4-di-dimethylaminophenylmethyl, 3,5-di-dimethylaminophenylmethyl or 3,6-di-dimethylaminophenylmethyl. More preferred examples are phenylmethyl (benzyl), phenylethyl, 2-cyanophenylmethyl, 3-cyanophenylmethyl, 4-cyanophenylmethyl, 2-dimethylaminophenylmethyl, 3-dimethylaminophenylmethyl or 4-dimethylaminophenylmethyl.
Aryl in CH(OH)-aryl for the substituent A is as defined above, preferably phenyl, naphtyl or an optionally substituted phenyl group. Suitable substituents for aryl can be selected from 1, 2, 3, 4 or 5 of C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine, preferably 1, 2 or 3 residues of methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine. Preferred aryl in CH(OH)-aryl for the substituent A is phenyl.
Aryl in CH(F)-aryl for the substituent A is as defined above, preferably phenyl, naphtyl or an optionally substituted phenyl group. Suitable substituents for aryl can be selected from 1, 2, 3, 4 or 5 of C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine, preferably 1, 2 or 3 residues of methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine. Preferred aryl in CH(OH)-aryl for the substituent A is phenyl.
Aryl in CHxe2x95x90CH-aryl for the substituent A is as defined above, preferably phenyl or an optionally substituted phenyl group. The ethenediyl group (xe2x80x94CHxe2x95x90CHxe2x80x94) can have the (E) or (Z) configuration. Both isomeric forms of these compounds are embraced by the present invention. The preferred configuration of the ethenediyl group within the invention is the (E) configuration. Suitable substituents for aryl can be selected from 1, 2, 3, 4 or 5 of C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine, preferably 1, 2 or 3 residues of methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine. Preferred aryl in CHxe2x95x90CH-aryl for the substituent A is phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl or 4-chlorophenyl. Most preferred aryl in CHxe2x95x90CH-aryl for the substituent A is phenyl.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein denotes an aryl or an optionally substituted aryl group as defined above which is bonded to an alkoxy group containing 1 to 4 carbon atoms as defined above. Preferred examples are phenyl-methyl-oxy (phenylmethoxy or benzyloxy), 4-methylphenylmethoxy, 4-methoxyphenylmethoxy, 4-fluorophenylmethoxy or 4-chlorophenylmethoxy. Most preferred example is phenyl-methyl-oxy.
The term xe2x80x9carylalkylaminoxe2x80x9d as used herein denotes a group of formula N(R)xe2x80x94C1-4-alkyl-aryl wherein an aryl or an optionally substituted aryl group as defined above is bonded to an alkyl group containing 1 to 4 carbon, which is bonded to an amino group. The amino group is also substituted with R, wherein R is a hydrogen or unsubstituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms. An example is phenyl-methyl-amino(methyl) (benzylaminomethyl).
The term xe2x80x9cheterocyclylxe2x80x9d as used herein denotes optionally substituted aromatic or non-aromatic monocyclic or bicyclic heterocycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulfur. Also included within the present invention are heterocyclyl compounds with an oxo (xe2x95x90O) group. Examples of suitable heterocycles are furyl, 1-pyrrolyl, 2-pyrrolyl, 1-thiophenyl, 2-thiophenyl, 2-pyridinyl (2-pyridyl), 3-pyridinyl (3-pyridyl), 4-pyridinyl (4-pyridyl), 1H-pyridin-2-one, 1H-pyridin-4-one, 3H-pyrimidine-4-one, pyridazine (1,2-diazine), pyrimidine (1,3-diazine), pyrazine (1,4-diazine), oxazole or isoxazole (iso-oxazole).
Suitable substituents for heterocyclyl can be selected from, 1, 2, 3 or 4 (where chemically possible), more preferred 1, 2 or 3, most preferred 1 or 2 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl. The substituents for substituted heterocyclyl may also be selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, cyano, fluorine, chlorine and bromine, or the substituents may optionally be selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine and bromine. In case more than one substituent is attached to the heterocyclyl group, these substituents can be identical or different from each other. For all the cited examples for xe2x80x9cheterocyclylxe2x80x9d these substituents can be at any chemically possible position. For example methylpyridyl means that the methyl substituent may be attached in the 3, 4, 5 or 6 position of a 2-pyridyl or in the 2, 4, 5 or 6 position of a 3-pyridyl or in the 2, 3, 5 or 6 position of a 4-pyridyl.
The term xe2x80x9cC1-4-alkyl substituted with heterocyclylxe2x80x9d as used herein for the substituent A denotes a C1-4-alkyl as defined above which is substituted with a heterocyclyl group or with a substituted heterocyclyl group which is substituted with 1, 2, 3 or 4 (where chemically possible), more preferred 1, 2 or 3, most preferred 1 or 2 of those substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl. The substituents for substituted heterocyclyl may also be selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine and bromine. Within the invention C1, C1-2-and C3-4-alkyl substituted with optionally substituted heterocyclyl are preferred. Examples are furylmethyl, furylethyl, furylpropyl, furylbutyl, methylfurylmethyl, methylfurylethyl, dimethylfurylmethyl, ethylfurylmethyl, methoxyfurylmethyl, methoxyfurylethyl, dimethoxyfurylmethyl, hydroxyfurylmethyl, hydroxyfurylethyl, dihydroxyfurylmethyl, fluorofurylmethyl, difluorofurylmethyl, chloro furylmethyl, chlorofurylethyl, dichlorofurylmethyl, dichlorofurylmethyl, bromofurylmethyl, dibromofurylmethyl, pyrrolylmethyl, pyrrolylethyl, pyrrolylpropyl, pyrrolylbutyl, methylpyrrolylmethyl, methylpyrrolylethyl, dimethylpyrrolylmethyl, ethylpyrrolylmethyl, methoxypyrrolylmethyl, methoxypyrrolylethyl, dimethoxypyrrolylmethyl, hydroxypyrrolylmethyl, hydroxypyrrolylethyl, dihydroxypyrrolylmethyl, fluoropyrrolylmethyl, difluoropyrrolylmethyl, chloropyrrolylmethyl, chloropyrrolylethyl, dichloropyrrolylmethyl, dichloropyrrolylmethyl, bromorpyrrolylmethyl, dibromopyrrolylmethyl, thiophenylmethyl (2-thiophenylmethyl, 3-thiophenylmethyl), thiophenylethyl, thiophenylpropyl, thiophenylbutyl, methylthiophenylmethyl, methylthiophenylethyl, dimethylthiophenylmethyl, ethylthiophenylmethyl, methoxythiophenylmethyl, methoxythiophenylethyl, dimethoxythiophenylmethyl, hydroxythiophenylmethyl, hydroxythiophenylethyl, dihydroxythiophenylmethyl, fluorothiophenylmethyl, difluorothiophenylmethyl, chlorothiophenylmethyl, chlorothiophenylethyl, dichlorothiophenylmethyl, dichlorothiophenylmethyl, bromorthiophenylmethyl, dibromothiophenylmethyl, pyridinylmethyl (2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl), pyridinylethyl, pyridinylpropyl, pyridinylbutyl, 3-methyl-2-pyridinylmethyl, 4-methyl-2-pyridinylmethyl, 5-methyl-2-pyridinylmethyl, 6-methyl-2-pyridinylmethyl, 2-methyl-3-pyridinylmethyl, 4-methyl-3-pyridinylmethyl, 5-methyl-3-pyridinylmethyl, 6-methyl-3-pyridinylmethyl, 24 methyl-4-pyridinylmethyl, 3-methyl-4-pyridinylmethyl, 5-methyl-4-pyridinylmethyl, 6-methyl-4-pyridinylmethyl, 3-m ethoxy-2-pyridinylmethyl, 4-methoxy-2-pyridinylmethyl, 5-methoxy-2-pyridinylmethyl, 6-methoxy-2-pyridinylmethyl, 2-methoxy-3-pyridinylmethyl, 4-methoxy-3-pyridinylmethyl, 5-methoxy-3-pyridinylmethyl, 6-methoxy-3-pyridinylmethyl, 2-methoxy-4-pyridinylmethyl, 3-methoxy-4-pyridinylmethyl, 5-methoxy-4-pyridinylmethyl, 6-methoxy-4-pyridinylmethyl, 3-fluoro-2-pyridinylmethyl, 4-fluoro-2-pyridinylmethyl, 5-fluoro-2-pyridinylmethyl, 6-fluoro-2-pyridinylmethyl, 2-fluoro-3-pyridinylmethyl, 4-fluoro-3-pyridinylmethyl, 5-fluoro-3-pyridinylmethyl, 6-fluoro-3-pyridinylmethyl, 2-fluoro-4-pyridinylmethyl, 3-fluoro-4-pyridinylmethyl, 5-fluoro-4-pyridinylmethyl, 6-fluoro-4-pyridinylmethyl, 3-chloro-2-pyridinylmethyl, 4-chloro-2-pyridinylmethyl, 5-chloro-2-pyridinylmethyl, 6-chloro-2-pyridinylmethyl, 2-chloro-3-pyridinylmethyl, 4-chloro-3-pyridinylmethyl, 5-chloro-3-pyridinylmethyl, 6-chloro-3-pyridinylmethyl, 2-chloro-4-pyridinylmethyl, 3-chloro-4-pyridinylmethyl, 5-chloro-4-pyridinylmethyl, 6-chloro-4-pyridinylmethyl, 3-bromo-2-pyridinylmethyl, 4-bromo-2-pyridinylmethyl, 5-bromo-2-pyridinylmethyl, 6-bromo-2-pyridinylmethyl, 2-bromo-3-pyridinylmethyl, 4-bromo-3-pyridinylmethyl, 5-bromo-3-pyridinylmethyl, 6-bromo-3-pyridinylmethyl, 2-bromo-4-pyridinylmethyl, 3-bromo-4-pyridinylmethyl, 5-bromo-4-pyridinylmethyl, 6-bromo-4-pyridinylmethyl, 3-cyano-2-pyridinylmethyl, 4-cyano-2-pyridinylmethyl, 5-cyano-2-pyridinylmethyl, 6-cyano-2-pyridinylmethyl, 2-cyano-3-pyridinylmethyl, 4-cyano-3-pyridinylmethyl, 5-cyano-3-pyridinylmethyl, 6-cyano-3-pyridinylmethyl, 2-cyano-4-pyridinylmethyl, 3-cyano-4-pyridinylmethyl, 5-cyano-4-pyridinylmethyl, 6-cyano-4-pyridinylmethyl, 3-(methylthio)-2-pyridinylmethyl, 4-(methylthio)-2-pyridinylmethyl, 5-(methylthio)-2-pyridinylmethyl, 6-(methylthio)-2-pyridinylmethyl, 2-(methylthio)-3-pyridinylmethyl, 4-(methylthio)-3-pyridinylmethyl, 5-(methylthio)-3-pyridinylmethyl, 6-(methylthio)-3-pyridinylmethyl, 2-(methylthio)-4-pyridinylmethyl, 3-(methylthio)-4-pyridinylmethyl, 5-(methylthio)-4-pyridinylmethyl, 6-(methylthio)-4-pyridinylmethyl, 2-chloro-3-methyl-4-pyridinylmethyl, 2-chloro-5-methyl-4-pyridinylmethyl, 2-chloro-6-methyl-4-pyridinylmethyl, 3-chloro-5-methyl-4-pyridinylmethyl, 3-chloro-6-methyl-4-pyridinylmethyl, 5-chloro-6-methyl-4-pyridinylmethyl, methylpyridinylethyl, dimethylpyridinylmethyl, ethylpyridinylmethyl, methoxypyridinylmethyl, methoxypyridinylethyl, dimethoxypyridinylmethyl, hydroxypyridinylmethyl, hydroxypyridinylethyl, dihydroxypyridinylmethyl, fluoropyridinylmethyl, difluoropyridinylmethyl, chioropyridinylmethyl, chloropyridinylethyl, dichloropyridinylmethyl, dichloropyridinylmethyl, fromorpyridinylmethyl, dibromopyridinylmethyl, indolylmethyl, indolylethyl, indolylpropyl, indolylbutyl, methylindolylmethyl, methylindolylethyl, dimethylindolylmethyl, ethylindolylmethyl, methoxyindolylmethyl, methoxyindolylethyl, dimethoxyindolylmethyl, hydroxyindolylmethyl, hydroxyindolylethyl, dihydroxyindolylmethyl, fluoroindolylmethyl, difluoroindolylmethyl, chloroindolylmethyl, chloroindolylethyl, dichloroindolylmethyl, dichloroindolylmethyl, bromorindolylmethyl, dibromoindolylmethyl, 2-bromo-pyrimidin-4-yl, 5-bromo-pyrimidin-4-yl, 6-bromo-pyrimidin-4-yl, oxazolylmethyl, 3-methyl-oxazolylmethyl, 4-methyl-oxazolylmethyl, 5-methyl-oxazolylmethyl, 3,5-dimethyl-oxazolylmethyl, 3,4-dimethyl-oxazolylmeth, 1, 4,5-dimethyl-oxazolylmethyl, oxazolylmethyl or isoxazolylmethyl. Preferred examples are furylmethyl, furylethyl, pyrrolylmethyl, pyrrolylethyl, 4-pyridinylmethyl (2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl), 4-pyridinylethyl, indolylmethyl, indolylethyl, 2-bromo-pyrimidin-4-yl, 5-bromo-pyrimidin-4-yl, 6-bromo-pyrimidin-4-yl, thiophenylmethyl (2-thiophenylmethyl, 3-thiophenylmethyl), thiophenylethyl, 6-bromo-pyrimidin-4-yl, oxazolylmethyl, 3-methyl-oxazolylmethyl, 4-methyl-oxazolylmethyl, 5-methyl-oxazolylmethyl, 3,5-dimethyl-oxazolylmethyl, 3,4-dimethyl-oxazolylmethyl, 4,5-dimethyl-oxazolylmethyl, oxazolylmethyl, isoxazolylmethyl, 3-methoxy-4-pyridinylmethyl, 2-fluoro-4-pyridinylmethyl, 2-chloro-4-pyridinylmethyl, 3-chloro-4-pyridinylmethyl, 5-bromo-3-pyridinylmethyl, 3-cyano-2-pyridinylmethyl, 2-(methylthio)-3-pyridinylmethyl, 3-chloro-5-methyl-4-pyridinylmethyl, and most preferred examples are 4-pyridinylmethyl and 4-pyridinylethyl.
The formula xe2x80x9cCH2-U-heterocyclylxe2x80x9d as used herein for the substituent A denotes a heterocyclyl group as defined above, which is connected to the group xe2x80x9cUxe2x80x9d which represents O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl. The xe2x80x9cheterocyclyl-Uxe2x80x9d-moiety is connected to a methyl group. The above mentioned heterocyclyl group is optionally substituted with 1-4, preferred 1-3, more preferred 1-2 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl. Preferred examples for the xe2x80x9cheterocyclyl-Uxe2x80x9d-moiety are 4-pyridyl-oxy, 3-pyridyl-oxy, 2-pyridyl-oxy, 2-nitro-3-pyridyl-oxy, 2-amino-3-pyridyl-oxy, 4-methyl-3-pyridyl-oxy, 5-chloro-3-pyridyl-oxy, 2-amino-6-methyl-1,3-pyrimidin-4yl-oxy, 4-pyridyl-mercapto, 3-pyridyl-mercapto, 2-pyridyl-mercapto, 4-pyridyl-amino, 3-pyridyl-amino or 2-pyridyl-amino.
Heterocyclyl in CH(OH)-heterocyclyl for the substituent A is as defined above, preferably furyl, 1-pyrrolyl, 2-pyrrolyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl or an optionally substituted heterocyclyl group. Suitable substituents for heterocyclyl can be selected from 1, 2, 3 or 4 (where chemically possible) of C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine, preferably 1 or 2 of methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine. Preferred heterocyclyl in CH(OH)-heterocyclyl for the substituent A are 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.
Heterocyclyl in CH(F)-heterocyclyl for the substituent A is as defined above, preferably furyl, 1-pyrrolyl, 2-pyrrolyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl or an optionally substituted heterocyclyl group. Suitable substituents for heterocyclyl can be selected from 1, 2, 3 or 4 (where chemically possible) of C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine, preferably 1 or 2 of methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine. Preferred heterocyclyl in CH(OH)-heterocyclyl for the substituent A is 4-pyridinyl.
Heterocyclyl in CHxe2x95x90CH-heterocyclyl for the substituent A is as defined above, preferably pyridinyl or an optionally substituted pyridinyl group. The ethenediyl group (xe2x80x94CHxe2x95x90CHxe2x80x94) can have the (E) or (Z) configuration. Both isomeric forms of these compounds are embraced by the present invention. The preferred configuration of the ethenediyl group within the invention is the (E) configuration. Suitable substituents for heterocyclyl can be selected from 1, 2, 3 or 4 (where chemically possible) of C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine, preferably 1 or 2 of methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine. Preferred heterocyclyl in CHxe2x95x90CH-heterocyclyl for the substituent A is pyridinyl, 4-methylpyridinyl, 4-methoxypyridinyl, 4-fluoropyridinyl or 4-chloropyridinyl. Most preferred heterocyclyl in CHxe2x95x90CH-heterocyclyl for the substituent A is pyridinyl.
The term xe2x80x9cheterocyclylalkoxyxe2x80x9d as used herein denotes an aryl or an optionally substituted heterocyclyl group as defined above which is bonded to an alkoxy group containing 1 to 4 carbon atoms as defined above. Preferred examples are 4-pyridyl-methyl-oxy (4-pyridylmethoxy), 3-pyridyl-methyl-oxy (3-pyridylmethoxy), 2-pyridyl-methyl-oxy (2-pyridylmethoxy).
The term halogen stands for fluorine, chlorine, bromine and iodine. More preferred halogen is fluorine, chlorine or bromine and most preferred halogen is fluorine or chlorine.
Within the invention the term xe2x80x9cXxe2x80x9d represents S or O, preferably S.
Any functional (i.e. reactive) group present in a side-chain may be protected, with the protecting group being a group which is known per se, for example, as described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Ed., T. W. Greene and P. G. M. Wuts, John Wiley and Sons, New York, N.Y., 1991. For example, an amino group can be protected by tert.-butoxycarbonyl (BOC) or benzyloxycarbonyl (Z).
The compounds of this invention may contain one or more asymmetric carbon atoms and may therefore occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Furthermore, where a compound of the invention contains an olefinic double bond, this can have the (E) or (Z) configuration. Also, each chiral center may be of the R or S configuration. All such isomeric forms of these compounds are embraced by the present invention.
Compounds of formula I which are acidic can form pharmaceutically acceptable salts with bases such as alkali metal hydroxides, e.g. sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides, e.g. calcium hydroxide, barium hydroxide and magnesium hydroxide, and the like; with organic bases e.g. N-ethyl piperidine, dibenzylamine, and the like. Those compounds of formula I which are basic can form pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid, and the like, and with organic acids, e.g. with acetic acid, formic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulphonic acid and p-toluene sulphonic acid, and the like. The formation and isolation of such salts can be carried out according to methods known in the art.
A preferred embodiment of the invention is the use of compounds of formula I wherein 
R1 is optionally substituted C1-12-alkyl, C3-8-cycloalkyl, acyl, C1-4-alkylsulfonyl,
optionally substituted phenylsulfonyl, aryl, heterocyclyl or C1-4-alkyl substituted with optionally substituted phenyl,
wherein C1-12-alkyl may be substituted with 1-5 substituents selected from fluorine, chlorine and bromine, and
wherein phenyl may be substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine and cyano;
R2 is optionally substituted phenyl,
wherein phenyl may be substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano and nitro;
R3 is C1-2-alkyl or C1-4-alkoxy-C1-4-alkyl;
A is a group selected from CH2-(aryl-C1-4-alkylamino), CH2-(aryl-C1-4-alkoxy), CH2-(heterocyclyl-C1-4-alkoxy), C1-4-alkyl substituted with optionally substituted aryl or with optionally substituted heterocyclyl,
wherein aryl may be substituted with 1-5 substituents or heterocyclyl is substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
A is a group of formula CH2-U-heterocyclyl,
wherein U is O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl, and
wherein heterocyclyl is optionally substituted with 1-4 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
A is a group of formula CH(V)Z,
wherein V represents OH or F, and
wherein Z represents aryl or heterocyclyl; or
A is a group of formula CHxe2x95x90CHW,
wherein W represents optionally substituted aryl or optionally substituted heterocyclyl, and
wherein aryl may be substituted with 1-5 substituents or heterocyclyl may be substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, cyano, fluorine, chlorine and bromine;
X represents S or O;
for the treatment of diseases mediated by the human immunodeficiency virus (HIV) or for the preparation of a medicament for such treatment.
Further preferred embodiments of the invention is the use of compounds of formula I wherein
Rxe2x80x2 is optionally substituted C1-12-alkyl, C3-8-cycloalkyl, aryl, heterocyclyl or C1-4-alkyl substituted with phenyl,
wherein C1-12-alkyl may be substituted with 1-5 fluorine substituents,
preferred wherein
Rxe2x80x2 is optionally substituted C1-7-alkyl, C3-8-cycloalkyl, aryl, heterocyclyl or C1-4-alkyl substituted with phenyl,
wherein C1-7-alkyl maybe substituted with 1-3 fluorine substituents,
more preferred wherein
Rxe2x80x2 is optionally substituted C1-7-alkyl, C3-6-cycloalkyl, phenyl, pyridyl or benzyl,
wherein C1-7-alkyl may be substituted with 1-3 fluorine substituents,
most preferred wherein
Rxe2x80x2 is C1-7-alkyl;
R2 is substituted phenyl, substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy, fluorine, chlorine, bromine, cyano and nitro,
preferred wherein
R2 is substituted phenyl, substituted with 1-3 substituents selected from C1-4-alkyl, C1-4-alkoxy, fluorine, chlorine, bromine, cyano and nitro,
more preferred wherein
R2 is substituted phenyl, substituted with 1-3 substituents selected from, chlorine and cyano,
most preferred wherein
R2 is substituted phenyl, substituted with 1-3 substituents selected from chlorine and cyano;
R3 is C1-12-alkyl or C1-4-alkoxy-C1-4-alkyl,
preferred wherein
R3 is C1-7-alkyl or C1-4-alkoxy-C1-2-alkyl,
more preferred wherein
R3 is C1-7-alkyl or C1-2-alkoxy-C1-2-alkyl,
most preferred wherein
R3 is C1-7-alkyl;
A is a group selected from CH2-(aryl-C1-4-alkoxy),
CH2-(heterocyclyl-C1-4-alkoxy), C1-4-alkyl substituted with optionally substituted phenyl or with optionally substituted heterocyclyl,
wherein phenyl may be substituted with 1-5 substituents or heterocyclyl is substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
A is a group of formula CH2-U-heterocyclyl,
wherein U is O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl, and
wherein heterocyclyl is optionally substituted with 1-4 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
A is a group of formula CH(V)heterocyclyl,
wherein V represents OH or F; or
A is a group of formula CHxe2x95x90CHW,
wherein W represents optionally substituted aryl, substituted with 1-5 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy,
hydroxy, cyano, fluorine, chlorine and bromine,
preferred wherein
A is a group selected from CH2-(phenyl-C1-2-alkoxy),
CH2-(pyridyl-C1-2-alkoxy), C1-2-alkyl substituted with optionally substituted phenyl or with optionally substituted heterocyclyl,
wherein phenyl maybe substituted with 1-3 substituents or heterocyclyl is substituted with 1-2 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alklyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
A is a group of formula CH2-U-heterocyclyl,
wherein U is O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl, and
wherein heterocyclyl is optionally substituted with 1-2 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
A is a group of formula CH(F)heterocyclyl,
more preferred wherein
A is a group selected from CH2-(phenyl-C1-2-alkoxy),
CH2-(pyridyl-C1-2-alkoxy), C1-2-alkyl substituted with optionally substituted phenyl or with optionally substituted heterocyclyl,
wherein phenyl may be substituted with 1-3 substituents or heterocyclyl is substituted with 1-2 substituents and the substituents are selected from C1-2-alkyl) C1-2-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-2-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-2-alkyl; or
A is a group of formula CH(F)Z,
wherein Z represents heterocyclyl,
most preferred wherein
A is a group selected from CH2-(phenyl-C1-2-alkoxy),
CH2-(pyridyl-C1-2-alkoxy), C1-2-alkyl substituted with optionally substituted heterocyclyl,
wherein heterocyclyl is substituted with 1-2 substituents and the substituents are selected from C1-2-alkyl, C1-2-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-2-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-2-alkyl;
X represents S or O;
for the treatment of diseases mediated by the human immunodeficiency virus (HIV) r for the preparation of a medicament for such treatment.
Further preferred embodiments of the invention is the use of compounds of formula I wherein
R1 is C1-4-alkyl,
preferred wherein
R1 is ethyl or iso-propyl;
R2 is substituted phenyl, substituted with 1-3 chlorine substituents,
preferred wherein
R2 is 3,5-dichlorophenyl;
R3 is C1-4-alkyl,
preferred wherein
R3 is methyl;
A is a group C1-2-alkyl substituted with optionally substituted heterocyclyl,
wherein heterocyclyl is substituted with 1-2 substituents and the substituents are selected from C1-2-alkyl and chlorine,
preferred wherein
A is a group C1-2-alkyl substituted with optionally substituted heterocyclyl,
wherein heterocyclyl is substituted with 1-2 substituents and the substituents are selected from C1-2-alkyl and chlorine;
X represents S or O.
A more preferred embodiment of the invention is the use of compounds of formula I wherein
X represents S.
Also part of the present invention is the use of compounds of formula I 
R1 is C1-12-alkyl, C3-8-cycloalkyl, acyl, C1-4-alkylsulfonyl, optionally substituted phenylsulfonyl, aryl or C1-4-alkyl substituted with optionally substituted phenyl,
wherein phenyl may be substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine and bromine;
R2 is aryl or optionally substituted phenyl,
wherein phenyl maybe substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine and bromine;
R3 is C1-2-alkyl or C1-4-alkoxy-C1-4-alkyl;
A is a group selected from CH2-(aryl-C1-4-alkylamino), CH2-(aryl-C1-4-alkoxy),
C1-4-alkyl substituted with optionally substituted aryl or with optionally substituted heterocyclyl,
wherein aryl may be substituted with 1-5 substituents or heterocyclyl is substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine and bromine; or
A is a group of formula CH(OH)Z,
wherein Z represents aryl or heterocyclyl; or
A is a group of formula CHxe2x95x90CHW,
wherein W represents optionally substituted aryl or optionally substituted heterocyclyl; and
wherein aryl may be substituted with 1-5 substituents or heterocyclyl may be substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine and bromine;
X represents S or O;
for the treatment of diseases mediated by the human immunodeficiency virus (HIV) or for the preparation of a medicament for such treatment.
More preferred embodiments for the use of compound of formula I for the treatment of diseases mediated by the human immunodeficiency virus (HIV) or for the preparation of a medicament for such treatment are set out in table 1 (see below):
Also part of the present invention are novel pyrazole derivatives, a process for their manufacture, pharmaceutical compositions and the use of such compounds in medicine. In particular, the compounds are inhibitors of the human immunodeficiency virus reverse transcriptase enzyme which is involved in viral replication.
The novel compounds of this invention are compounds of formula I-A 
wherein
R1 is optionally substituted C1-12-alkyl, C3-8-cycloalkyl, acyl, C1-4-alkylsulfonyl, optionally substituted phenylsulfonyl, aryl, heterocyclyl or C1-4-alkyl substituted with phenyl,
wherein C1-2-alkyl maybe substituted with 1-5 substituents selected from fluorine, chlorine and bromine, and
wherein phenyl may be substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine and cyano;
R2xe2x80x2 is optionally substituted phenyl;
wherein phenyl may be substituted with 1-5 substituents selected from
C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano and nitro;
R3 is C1-2-alkyl or C1-4-alkoxy-C1-4-alkyl;
Axe2x80x2 is a group selected from CH2-(aryl-C1-4-alkylamino), CH2-(aryl-C1-4-alkoxy), CH2-(heterocyclyl-C1-4-alkoxy), C1-4-alkyl substituted with optionally substituted aryl or with optionally substituted 4-pyridyl,
wherein aryl may be substituted with 1-5 substituents or 4-pyridyl is substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl,
C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
Axe2x80x2 is a group of formula CH2-U-heterocyclyl,
wherein U is O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl, and
wherein heterocyclyl is optionally substituted with 1-4 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
Axe2x80x2 is a group of formula CH(OH)aryl; or
Axe2x80x2 is a group of formula CHxe2x95x90CHW
wherein W represents optionally substituted aryl or optionally substituted heterocyclyl; and
wherein aryl may be substituted with 1-5 substituents or heterocyclyl may be substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, cyano, fluorine, chlorine and bromine;
X represents S or O;
hydrolyzable esters or ethers thereof, and pharmaceutically acceptable salts thereof.
The terms used for the substituents of novel pyrazole derivatives are as defined above.
Further embodiments of the invention are novel compounds of formula I-A wherein
R1 is optionally substituted C1-2-alkyl, C3-8-cycloalkyl, aryl, heterocyclyl or C1-4-alkyl substituted with phenyl,
wherein C1-12-alkyl maybe substituted with 1-5 fluorine substituents,
preferred wherein
R1 is optionally substituted C1-7-alkyl, C3-8-cycloalkyl, aryl, heterocyclyl or C1-4-alkyl substituted with optionally substituted phenyl,
wherein C1-7-alkyl may be substituted with 1-3 fluorine substituents, more preferred wherein
R1 is optionally substituted C1-7-alkyl, C3-8-cycloalkyl, phenyl, pyridyl or benzyl,
wherein C1-7-alkyl may be substituted with 1-3 fluorine substituents,
most preferred wherein
Rxe2x80x2 is C1-7-alkyl;
R2xe2x80x2 is substituted phenyl, substituted with 1-5 substituents selected from
C1-4-alkyl, C1-4-alkoxy, fluorine, chlorine, bromine, cyano and nitro,
preferred wherein
R2xe2x80x2 is substituted phenyl, substituted with 1-3 substituents selected from
C1-4-alkyl, C1-4-alkoxy, fluorine, chlorine, bromine, cyano and nitro,
more preferred wherein
R2xe2x80x2 is substituted phenyl, substituted with 1-3 substituents selected from
C1-2-alkyl, fluorine, chlorine and cyano,
most preferred wherein
R2xe2x80x3 is substituted phenyl, substituted with 1-3 substituents selected from chlorine and cyano;
R3 is C1-12-alkyl or C1-4-alkoxy-C1-4-alcyl,
preferred wherein
R3 is C1-7-alkyl or C1-4-alkoxy-C1-2-alkyl,
more preferred wherein
R3 is C1-7-alkyl or C1-2-alkoxy-C1-2-alkyl,
most preferred wherein
R3 is C1-7-alkyl;
Axe2x80x2 is a group selected from CH2-(phenyl-C1-4-alkoxy),
CH2-(pyridyl-C1-4-alkoxy), C1-4-alkyl substituted with optionally substituted aryl or with optionally substituted 4-pyridyl,
wherein aryl may be substituted with 1-5 substituents or 4-pyridyl is substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl,
C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
Axe2x80x2 is a group of formula CH2-U-heterocyclyl,
wherein U is O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl, and
wherein heterocyclyl is optionally substituted with 1-4 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
Axe2x80x2 is a group of formula CH(OH)aryl; or
Axe2x80x2 is a group of formula CHxe2x95x90CHW
wherein W represents optionally substituted aryl, substituted with 1-5 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, cyano, fluorine, chlorine and bromine,
preferred wherein
Axe2x80x2 is a group selected from CH2-(phenyl-C1-2-alkoxy),
CH2-(pyridyl-C1-2-alkoxy), methyl substituted with optionally substituted phenyl or with optionally substituted 4-pyridyl,
wherein phenyl may be substituted with 1-3 substituents or 4-pyridyl is substituted with 1-2 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
Axe2x80x2 is a group of formula CH2-U-heterocyclyl,
wherein U is O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl, and
wherein heterocyclyl is optionally substituted with 1-2 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl,
more preferred wherein
Axe2x80x2 is a group selected from CH2-(phenyl-C1-2-alkoxy),
CH2-(pyridyl-C1-2-alkoxy), methyl substituted with optionally substituted phenyl or with optionally substituted 4-pyridyl,
wherein phenyl may be substituted with 1-3 substituents or 4-pyridyl is substituted with 1-2 substituents and the substituents are selected from C1-2-alkyl, C1-2-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-2-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-2-alkyl,
most preferred wherein
Axe2x80x2 is a group selected from CH2-(aryl-C1-2-alkoxy),
CH2-(heterocyclyl-C1-2-alkoxy), methyl substituted optionally substituted 4-pyridyl,
wherein 4-pyridyl is substituted with 1-2 substituents and the substituents are selected from C1-2-alkyl, C1-2-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-2-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-2-alkyl;
X represents S or O;
hydrolyzable esters or ethers thereof, and pharmaceutically acceptable salts thereof
Another preferred embodiment of the invention are novel compounds of formula I-A
wherein
R1 is C1-4-alkyl;
R2xe2x80x2 is substituted phenyl, substituted with 1-3 chlorine substituents;
R3 is C1-4-alkyl;
Axe2x80x2 is a group methyl substituted optionally substituted 4-pyridyl,
wherein 4-pyridyl is substituted with 1-2 substituents and the substituents are selected from C1-2-alkyl and chlorine;
X represents S or O;
hydrolyzable esters or ethers thereof, and pharmaceutically acceptable salts thereof.
A further preferred embodiment of the invention are novel compounds of formula I-A wherein
R1 is C1-12-alkyl, C3-8-cycloalkyl, acyl, C1-4-alkylsulfonyl, optionally substituted phenylsulfonyl, aryl or C1-4-alkyl substituted with optionally substituted phenyl wherein phenyl may be substituted with 1-5 substituents selected from
C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine;
R2 is optionally substituted phenyl;
wherein phenyl may be substituted with 1-5 substituents selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine;
R3 is C1-2-alkyl or C1-4-alkoxy-C1-4-alkyl;
Axe2x80x2 is a group selected from CH2-(aryl-C1-4-alkylamino), CH2-(aryl-C1-4-alkoxy),
C1-4-alkyl substituted with optionally substituted aryl or with optionally substituted 4-pyridyl
wherein aryl may be substituted with 1-5 substituents or 4-pyridyl is substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine; or
Axe2x80x2 is a group of formula CH(OH)Zxe2x80x2
wherein Zxe2x80x2 represents aryl; or
Axe2x80x2 is a group of formula CHxe2x95x90CHW
wherein W represents optionally substituted aryl or optionally substituted heterocyclyl; and
wherein aryl may be substituted with 1-5 substituents or heterocyclyl may be substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine or bromine;
X represents S or O;
hydrolyzable esters or ethers thereof, and pharmaceutically acceptable salts thereof.
A preferred embodiment of the invention are novel compounds of formula I-A
wherein
Axe2x80x2 is a group selected from CH2-(aryl-C1-4-alkylamino), CH2-(aryl-C1-4-alkoxy),
CH2-(heterocyclyl-C1-4-alkoxy), C1-4-alkyl substituted with optionally substituted,
wherein aryl may be substituted with 1-5 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, fluorine, chlorine, bromine, cyano, Sxe2x80x94C1-4-alkyl and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
Axe2x80x2 is a group of formula CH2-U-heterocyclyl,
wherein U is O, S or NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-4-alkyl, and
wherein heterocyclyl is optionally substituted with 1-4 substituents selected from C1-4-alkyl, fluorine, chlorine, bromine, cyano, nitro and NRRxe2x80x2, wherein R and Rxe2x80x2 are independently of each other hydrogen or C1-4-alkyl; or
Axe2x80x2 is a group of formula CH(OH)aryl; or
Axe2x80x2 is a group of formula CHxe2x95x90CHW
wherein W represents optionally substituted aryl or optionally substituted heterocyclyl; and
wherein aryl may be substituted with 1-5 substituents or heterocyclyl may be substituted with 1-4 substituents and the substituents are selected from C1-4-alkyl, C1-4-alkoxy, hydroxy, cyano, fluorine, chlorine and bromine;
X represents S or O;
hydrolyzable esters or ethers thereof, and pharmaceutically acceptable salts thereof
An especially preferred embodiment of the invention are novel compounds of formula I-A wherein
X represents S.
More preferred embodiments of the invention are novel compounds of formula I-A set out in table 1 (see above):
The pyrazole derivatives provided by the present invention are useful in therapeutic treatment of the human or animal body, specifically the compounds are inhibitors of the human immunodeficiency virus reverse transcriptase enzyme. Accordingly, the present pyrazole derivatives are therapeutically active substances in the treatment of diseases mediated by the human immunodeficiency virus (HIV) and can be used as medicaments for the treatment of such diseases.
They can be used as medicaments, especially for treating viral diseases, immune mediated conditions or diseases, bacterial diseases, parasitic diseases, inflammatory diseases, hyperproliferative vascular diseases, tumors and cancer.
In particular, compounds of the present invention and pharmaceutical compositions containing the same are useful as chemotherapeutic agents, inhibitors of viral replication and modulators of the immune system, and can be used for the treatment of diseases mediated by the human immunodeficiency virus (HIV) other viral diseases such as retroviral infections (either alone or in combination with other antiviral agents such as interferon or derivatives thereof, such as conjugates with polyethylene glycol).
They can be used alone, or in combination with other therapeutically active agents, for example, an immunosuppressant, a chemotherapeutic agent, an anti-viral agent, an antibiotic, an anti-parasitic agent, an anti-inflammatory agent, an anti-fungal agent and/or an anti-vascular hyperproliferation agent.
Compounds, whenever prepared by the processes of the present invention are also an object of the present invention.
The compounds of the present invention can be prepared as shown in the following reaction schemes. The reactions can be carried out in a conventional manner known to those skilled in the art. The starting compounds required for the manufacture of the compounds of formula I are commercially available or can be prepared readily according to methods known in the art.
In the present specification xe2x80x9ccomprisexe2x80x9d means xe2x80x9cincludesxe2x80x9d and xe2x80x9ccomprisingxe2x80x9d means xe2x80x9cincludingxe2x80x9d. 
wherein R1, R2, R3 and X are as defined for compounds of formula I and R5 is aryl or heterocyclyl.
In reaction scheme 1, the first reaction step is carried out in that 5-hydroxy pyrazole derivatives of formula II (commercially available or synthesized in a conventional manner known to the skilled in the art as described in e.g. WO 9842678 or J. DeRuiter et al., J. Heterocyclic Chem., 1987, 24, 149) are reacted with R5COCl (commercially available or synthesized according to methods known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) wherein R5 is as defined above in an appropriate solvent to obtain a 4-substituted oxo 5-hydroxy pyrazole derivative of formula III. The reaction is conveniently carried out under conditions known from acylation reactions for example in an inert solvent, such as ethers e.g. anhydrous tetrahydrofuran, diethyl ether, dibutyl ether, dioxane, preferably dioxane, or a mixture of the mentioned solvents, at a reaction temperature from room temperature to boiling temperature of the reaction mixture in the presence of a catalyst such as Ca(OH)2, K2CO3, AlCl3, BF3, FeCl3, SnCl4 or ZnCl2, preferably Ca(OH)2.
In the second step of the reaction, the 5-hydroxy position of compounds of formula III is chlorinated with a chlorinating agent such as (COCI)2, HCl, PCl5, PCl3, SOCl2 or POCl3 to obtain 5-chloro-pyrazole derivatives of formula IV. The reaction is conveniently carried out under an inert atmosphere such as nitrogen or argon atmosphere at a reaction temperature from room temperature to boiling temperature of the reaction mixture. Preferably, the reaction is carried out in the presence of POCl3 at a reaction temperature between about 50xc2x0 C. and about 180xc2x0 C. Optionally, the reaction can be carried out in an organic solvent such as halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cyclohexane, methyl cyclohexane, decaline, benzene, toluene, o-xylene, m-xylene or p-xylene) or a mixtures of the mentioned solvents.
In the third step of the reaction, compound of formula IV is reacted with R2SH or with R2OH (both agents are commercially available or can be synthesized according to methods known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) wherein R2 is as defined for compounds of formula I to obtain the pyrazole derivative of formula V. The reaction is carried out in an appropriate solvent in the presence of a base such as such as n-BuLi, sodium hydride, trialkylamine such as trimethylamine or triethylamine, potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, preferably potassium carbonate. The reaction is conveniently carried out under an inert atmosphere such as nitrogen or argon atmosphere at a reaction temperature from 0xc2x0 C. to boiling temperature of the reaction mixture, preferably at a reaction temperature between about 10xc2x0 C. and about 180xc2x0 C. Appropriate solvents for the reaction are THF or polar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF.
In the fourth step of the reaction, the oxo group of compound of formula V is reduced to obtain the corresponding hydroxy compound of formula Ia. The reaction is conveniently carried out with a base such as sodium borohydride, lithium borohydride or preferably sodium borohydride in an organic solvent for example alcoholic solvents such as methanol, ethanol, propanol, butanol, octanol or cyclohexanol, preferably methanol or ethers (e.g. tetrahydrofuran, diethyl ether, dibutyl ether, dioxane or diglyme) at a reaction temperature from 0xc2x0 C. to boiling temperature of the reaction mixture, preferably at a reaction temperature between about 5xc2x0 C. and about 80xc2x0 C. The reduction reaction is carried out as it is described in textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons).
In the fifth step of the reaction, the methyl hydroxy group of compound of formula Ia is further reduced to the corresponding methylene group to obtain the compound of formula Ib. The reaction is conveniently carried out in the presence of trialkylsilane such as trimethylsilane, triethylsilane or tripropylsilane, preferably triethylsilane dissolved in mineral acids such as trifluoroacetic acid (TFA) or in Lewis acids such as SnCl4 (described in D. L. Comins et al., Tet. Lett., 1986, 27, 1869) at a reaction temperature from 0xc2x0 C. to 80xc2x0 C., preferably at a reaction temperature between about 5xc2x0 C. and about 50xc2x0 C.
The reduction reaction can also be carried out in the presence of NaI, (CH3)3SiCl and HBr or as described in textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). When the hydroxy group is converted into a leaving group such as a mesylate or sulphonate, preferably a mesylate, the reaction can then be carried out in the presence of Zn and acetic acid (described in J. E. Lynch et al., J. Org. Chem., 1997, 62, 9223-9228).
Optionally, the oxo derivative of compound of formula V is directly reduced to the corresponding methylene compound of formula Ib. Such methods for the direct reduction are for example the Clemmensen reduction, the Wolff-Kishner reduction, hydogenolysis of thioacetals or reduction using trialkylsilane such as trimethylsilane, triethylsilane or tripropylsilane, preferably triethylsilane dissolved in mineral acids such as trifluoroacetic acid (TFA).
In the sixth step of the reaction, the methyl hydroxy group of compound of formula Ia is converted into the corresponding fluoromethylene group to obtain the compound of formula Iz. The reaction is carried out by treatment of the compound of formula Ia with a suitable fluorinating agent such as a dialkylaminosuphur trifluoride (R7)2NSF3 of formula XIV, wherein R7 can be C1-4-alkyl (e.g. ethyl) or (R7)2N can be a cyclic amino group (e.g. morpholine). The fluorinating agent is commercially available (e.g. diethylamino sulfur trifluoride (DAST)) or can be synthesized according to known methods in the art. The fluorinating reaction can be carried out as described in textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). 
wherein R1, R2, R3, U and X are as defined for compounds of formula I, R5, R6 and R8 are aryl or heterocyclyl and R9 is CH2-(aryl-C1-4-alkylamino).
In reaction scheme 2, the first reaction step is carried out in that 5-hydroxy pyrazole derivatives of formula II (commercially available or synthesized in a conventional manner known to the skilled in the art as described in e.g. WO 9842678 or J. DeRuiter et al., J. Heterocyclic Chem., 1987, 24, 149) are converted to 4-carbaldehyde 5-chloro pyrazole derivatives of formula VI. The reaction which includes a hydroxy/chlorine exchange in the 5-position and the introduction of a C(xe2x95x90O)H group in the 4-position of the pyrazole is conveniently carried out with disubstituted formamide such as N,N-dimethylformamide, N,N-methylphenylformamide or N,N-diphenylformamide in the presence of POCl3 according the Vilsmeier reaction. The reaction is carried out under an inert atmosphere such as nitrogen or argon atmosphere at a reaction temperature from room temperature to boiling temperature of the reaction mixture, preferably at a reaction temperature between about 50xc2x0 C. and about 150xc2x0 C. Optionally, the reaction can be carried out in an inert organic solvent such as ethers (e.g. tetrahydrofuran, diethyl ether, dibutyl ether or dioxane), polar aprotic solvents such as dimethylsulfoxide (DMSO) or dimethylacetamide N, halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cydohexane, methyl cyclohexane, decaline, benzene, toluene, o-xylene, m-xylene or p-xylene) or a mixtures of the mentioned solvents. The chlorinating reaction can also be carried out according the method described for reaction scheme 1 (step 2) with chlorinating agent such as (COCI)2, HCl, PCl5, PCl3 or SOCl2. The introduction of the C(xe2x95x90O)H group (formylation reaction) to the pyrazole derivative can also be carried out according to methods known from organic textbooks (J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). Such methods are for example Friedel-Crafts reaction, Vilsmeier-Haack reaction, Gattermann reaction, Gattermann-Koch reaction, Hoeben-Hoesch reaction or Reimer-Tiemann reaction.
In the second step of the reaction, compound of formula VI is reacted with R2SH or with R2OH (both agents are commercially available or can be synthesized according to methods known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) wherein R2 is as defined for compounds of formula I to obtain the pyrazole derivative of formula VII. The reaction is carried out according the method described for reaction scheme 1 (step 3).
In the third step of the reaction, the aldehyde function of compound of formula VII is reacted via a Wittig-Horner reaction with dialkyl phosphonate of formula (EtO)2P(xe2x95x90O)(CH2)nR6 wherein n is a number 1, 2 or 3 to olefinic compound of formula Ic. The reaction is carried out similar the method described in the literature, for example in the presence of a strong base such as n-BuLi or preferably sodium hydride in an organic solvent for example anhydrous ethers such as diethyl ether, dibutyl ether, dioxane, preferably anhydrous tetrahydrofuran under inert atmosphere such as nitrogen or argon atmosphere at a reaction temperature from 0xc2x0 C. to 80xc2x0 C., preferably at a reaction temperature between about 5xc2x0 C. and about 50xc2x0 C. Optionally, olefinic compound of formula Ic can be obtained through other coupling reactions for example the Wittig reaction.
In the fourth step of the reaction, the olefinic group of compound of formula Ic is hydrogenated to the corresponding compound of formula Id. The reaction is carried out similar to methods described in the literature, for example under hydrogen in the presence of a hydrogenation catalyst in an appropriate solvent at a reaction temperature from 0xc2x0 C. to 80xc2x0 C., preferably at a reaction temperature between about 5xc2x0 C. and about 50xc2x0 C. The hydrogen pressure can be between about 0 atm and about 100 atm, preferably between about 0 atm and about 50 atm and most preferred between about 0 atm and about 20 atm. The hydrogenation catalyst used for this reaction can be one of the commonly known catalysts such as noble metals (e.g. Pt, Pd or Rh) on supporting materials such as activated carbon or Al2O3, or generally as described in textbooks about organic chemistry e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). Preferred hydrogenation catalysts are Pd on activated carbon or Raney-Nickel. Appropriate solvents for the hydrogenation reaction are organic solvent such as alcohols (e.g. methanol, ethanol, propanol, butanol, octanol or cyclohexanol), ethers (e.g. tetrahydrofuran, diethyl ether, dibutyl ether or dioxane), ketones (e.g. acetone, butanone or cyclohexanone), polar aprotic solvents such as dimethylsulfoxide (DMSO) or dimethylacetamide N, esters (e.g. ethyl acetate), halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cyclohexane, methyl cyclohexane, decaline, benzene, toluene, o-xylene, m-xylene or p-xylene) or a mixtures of the mentioned solvents. Preferred solvents are ester, most preferred solvent is ethyl acetate.
In the fifth step of the reaction, the pyrazole of formula VII is derivatised with a Grignard reagent R5MgHal of formula XV, wherein R5 is aryl or heterocyclyl as defined for compounds of formula I and Hal represents chlorine, bromine or iodine, preferably chlorine (commercially available or synthesised according to textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms and Structurexe2x80x9d, 4th ed. John Wiley and Sons) to obtain the corresponding substituted hydroxy-methyl-pyrazole derivative of formula Ia. The derivatisation reaction is conveniently carried out in an inert solvent for example ethers such as tetrahydrofuran, diethyl ether, dibutyl ether, dioxane, diglyme or a mixture of the mentioned solvents, preferably tetrahydrofuran at a reaction temperature between about xe2x88x9210xc2x0 C. and about 60xc2x0 C., preferably at a reaction temperature between about 0xc2x0 C. and about 40xc2x0 C., more preferred at room temperature. In general, the derivatisation reaction can also be carried out as described in textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons. Instead of a Grignard reagent R5MgHal of formula XV the corresponding lithium reagent of formula LiR5 can be used as well.
In the sixth step of the reaction, the reduction reaction is carried out as described in reaction scheme 1 (step 5) or can also be carried in the presence P2I4 as described in EP 0627423.
For the synthesis of compounds of formula I wherein R1, R2, R3 and X are as defined in claim 1 and A is CH2-(aryl-C1-4-alkoxy) or CH2-(heterocyclyl-C1-4-alkoxy), compounds of formula VII are converted via a reduction and subsequent etherification reaction to the corresponding compounds of formula I wherein R1, R2, R3 and X are as defined in claim 1 and A is CH2-(aryl-C1-4-alkoxy) or CH2-(heterocyclyl-C1-4-alkoxy). Both reactions are known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). For example compounds of formula VII are first reduced with an appropriate reducing agent (e.g. NaBH4 in an alcoholic solvent such as methanol) to the corresponding alcohol derivative and secondly reacted with an aryl-C1-4 alkyl-halide or heterocyclyl-C1-4 alkyl-halide under basic conditions (e.g. NaH in a polar aprotic solvent such as DMF) to the corresponding compounds of formula I wherein R1, R2, R3 and X are as defined in claim 1 and A is CH2-(aryl-C1-4-alkoxy) or CH2-(heterocyclyl-C1-4-alkoxy).
The above reaction is described in more detail in steps 7-9.
In the seventh step of the reaction, the aldehyde of formula VII is reduced in the presence of a reducing agent to obtain the corresponding hydroxy-methyl derivative of formula XVI. Reducing agents conveniently used for the reaction are preferably sodium borohydride or other reducing agents such as lithium borohydride, sodium triacetoxyborohydride, hydrogen over a catalyst or reducing agents known in the art applied according to known methods described in textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms and Structurexe2x80x9d, 4th ed. John Wiley and Sons. The reduction reaction is conveniently carried out in an organic solvent for example alcoholic solvents such as methanol, ethanol, propanol, butanol, octanol or cyclohexanol, preferably methanol or ethanol or ethers such as tetrahydrofuran, diethyl ether, dibutyl ether, dioxane or diglyme, preferably tetrahydrofuran or a mixture of the mentioned solvents such as methanol and tetrahydrofuran or ethanol and tetrahydrofuran. The reaction is carried out at a reaction temperature between about xe2x88x9210xc2x0 C. and about 60xc2x0 C., preferably at room temperature. The reduction reaction can also be carried out as described in textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons.
In the eighth step of the reaction, the hydroxy-methyl function of compound of formula XVI is converted to the corresponding bromo-methyl derivative of formula XVII according to standard procedures according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons. A possible method for the preparation of a bromide derivative of formula XVII is by using tetrabromomethane in the presence of triphenylphosphine in dichloromethane, at room temperature.
In the ninth step of the reaction, the bromide of formula XVII is reacted with an arylmethanol or a heterocyclyl-methanol compound HOCH2R8 of formula XVIII to obtain the corresponding pyrazole derivative of formula Iy. The reaction is conveniently carried out according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms and Structurexe2x80x9d, 4th ed. John Wiley and Sons). The reaction is for example carried out in the presence of a base such as sodium hydride, lithium hydride, potassium carbonate or triethylamine in an appropriate organic solvent such as tetrahydrofuran (THF) or polar aprotic solvents like dimethylsulfoxide (DMSO), N,N-dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF or THF, at a reaction temperature between about xe2x88x9210xc2x0 C. and about 60xc2x0 C., preferably at room temperature.
In the tenth step of the reaction, the bromide, the hydroxy-methyl pyrazole derivative BrCH2R8 of formula XVI is directly converted to the corresponding pyrazole derivative of formula Iy. The reaction is carried out according to standard procedures according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons. A possible method for the preparation of the pyrazole derivative of formula Iy is the reaction of the hydroxy-methyl pyrazole derivative of formula XVI with an arylmethylbromide or a heterocyclyl-methylbromide compound of formula XIX in the presence of a base. The reaction may be preferably carried out in an organic solvent such as polar aprotic solvents like N,N-dimethylacetamide or N,N-dimethylformamide (DMF), dichloromethane or tetrahydrofuran using a base such as sodium hydride, lithium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate or organic amines such as triethylamine, morpholine or an N-alkyl morpholine such as N-methylmorpholine at a reaction temperature between about xe2x88x9210xc2x0 C. and about 60xc2x0 C., preferably at room temperature.
In the eleventh step of the reaction, the hydroxy-methyl pyrazole derivative of formula XVI is converted via a Mitsunobu reaction to the corresponding compounds of formula Ix. The reaction is known to those skilled in the art (D. L. Hughes, Organic Preparations and Procedures International, 1996, 28, 127; 0. Mitsunobu, Synthesis 1981, 1). The reaction is carried out in the presence of a trialkyl- or triarylphosphine, such as triphenylphosphine, and a reagent of formula RC(O)N=NC(O)R [R=alkoxy or dialkylamino], such as diethyl azodicarboxylate. The reaction is carried out in an appropriate organic solvent such as dichloromethane, tetrahydrofuran (THF) or polar aprotic solvents like N,N-dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF or THF, at a reaction temperature between about xe2x88x9210xc2x0 C. and about 60xc2x0 C., preferably at room temperature.
Compounds of formula Ix, wherein U is S are synthesized starting with bromomethyl intermediate XVII, using an alkylation reaction with a mercapto heterocycle (thio heterocycle of formula Het-SH). This reaction is carried out according to standard procedures according to methods known from textbooks on organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons. The reaction is preferably carried out in an organic solvent such as polar aprotic solvents like N,N-dimethylacetamide or N,N-dimethylformamide (DMF), dichloromethane or tetrahydrofuran using a base such as sodium hydride, lithium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate or organic amines such as triethylamine, morpholine or an N-alkyl morpholine such as N-methylmorpholine at a reaction temperature between about xe2x88x9210xc2x0 C. and about 60xc2x0 C., preferably at room temperature
In the twelfth step of the reaction, compound of formula VII is converted via a reductive amination reaction to the corresponding compounds of formula Iw wherein R1, R2, R3 and X are as defined in claim 1 and R9 is CH2-(aryl-C1-4-alkylamino). The reductive amination reaction is known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). For example compound of formula VII is reacted with an aryl amine derivative to the corresponding imine derivative and subsequently reduction reaction with for example NaBH(OAc)3 to yield the compounds of formula Iw wherein R1, R2, R3 and X are as defined in claim 1 and R9 is CH2-(aryl-C1-4-alkylamino). Optionally, the secondary amine can be alkylated with a C1-4-alkyl halide to the corresponding C1-4-alkylated compounds of formula Iw. The alkylation reaction is known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). 
wherein R1, R2, R3 and X are as defined for compounds of formula I and R5 is aryl or heterocyclyl.
In reaction scheme 3, the first reaction step is carried out in that p-CH3O(C6H4)CH2NHNH2.2HCl (preparation see example 3) is reacted with compounds of formula VIII to obtain pyrazole derivatives of formula IX. The reaction is conveniently carried out in the presence of a base for example potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, potassium hydroxide, sodium hydroxide, magnesium hydroxide, calcium hydroxide, N(CH3)3, N(C2H5)3, N(n-C3H7)3, N(i-C3H7)3, preferably a trialkyl amine, in an appropriate solvent such as halogenated hydrocarbons (e.g. dichloromethane or trichloromethane) or hydrocarbons (e.g. cyclohexane, methyl cyclohexane, decaline, benzene, toluene, o-xylene, m-xylene or p-xylene), preferably toluene. The reaction is carried out at a reaction temperature from room temperature to boiling temperature of the reaction mixture, preferably at a reaction temperature between about 50xc2x0 C. and about 150xc2x0 C.
In the second step of the reaction, compound of formula IX is reacted with R5COCl (commercially available or synthesized according to methods known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) wherein R5 is as defined above in an appropriate solvent to obtain a 4-substituted oxo pyrazole derivative of formula X. The reaction is carried out under the same conditions described for reaction scheme 1 (step 1).
In the third step of the reaction the 5-hydroxy position of compounds of formula X is chlorinated with a chlorinating agent such as (COCI)2, HCl, PCl5, PCl3, SOCl2 or POCl3 to obtain 5-chloro-pyrazole derivatives of formula XI. Conveniently the reaction can be carried out with POCl3 at a reaction temperature between about 0xc2x0 C. and about boiling temperature of the reaction mixture, preferably between about 5xc2x0 C. and about 100xc2x0 C. The reaction can optionally be carried out under an inert atmosphere such as nitrogen or argon atmosphere and in an organic solvent such as ethers (e.g. tetrahydrofuran, diethyl ether, dibutyl ether or dioxane), halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cyclohexane, methyl cyclohexane, decaline, benzene, toluene, o-xylene, m-xylene or p-xylene) or a mixtures of the mentioned solvents.
In the fourth step of the reaction, compound of formula XI is reacted with R2SH or with R2OH (both agents are commercially available or can be synthesized according to methods known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons) wherein R2 is as defined for compounds of formula I to obtain the pyrazole derivative of formula XII. The reaction is carried out in an appropriate solvent in the presence of a base such as n-BuLi, sodium hydride, trialkylamine such as trimethylamine or triethylamine, potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, preferably potassium carbonate. The reaction is carried out in an appropriate solvent in the presence of a base such as sodium hydride, trialkylamine such as trimethylamine or triethylamine, potassium carbonate, sodium carbonate, magnesium carbonate, calcium carbonate, preferably potassium carbonate. The reaction is conveniently carried out at a reaction temperature from 0xc2x0 C. to boiling temperature of the reaction mixture, preferably at a reaction temperature between room temperature and about 180xc2x0 C. Appropriate solvents for the reaction are THF or polar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF.
In the fifth step of the reaction, compound of formula XII is reacted with trifluoroacetic acid to remove the 4-methoxy-benzyl group of the pyrazole derivative and to yield to unprotected pyrazole compound of formula XIII. The reaction can also be carried out in mineral acids such as HCl in a suitable solvent such as dioxane, ether ethyl acetate or methanol. The reaction is conveniently carried out at a reaction temperature from room temperature to boiling temperature of the reaction mixture, preferably at a reaction temperature between 40xc2x0 C. and about 150xc2x0 C. The reaction can optionally be carried out under an inert atmosphere such as nitrogen or argon atmosphere and in an organic solvent such as alcohols (e.g. methanol, ethanol, propanol, butanol, octanol or cyclohexanol), ethers (e.g. tetrahydrofuran, diethyl ether, dibutyl ether or dioxane), ketones (e.g. acetone, butanone or cyclohexanone), esters (e.g. ethyl acetate), halogenated hydrocarbons (e.g. dichloromethane or trichloromethane), hydrocarbons (e.g. cyclohexane, methyl cyclohexane, decaline, benzene, toluene, o-xylene, m-xylene or p-xylene) or a mixtures of the mentioned solvents.
In the sixth step of the reaction, compound of formula XIII is reacted with an alkylating agent of formula R1L wherein L is a leaving group such as chlorine, bromine, iodine, mesylate or tosylate, to obtain N-substituted pyrazole derivative of formula V. The reaction is conveniently carried out in an appropriate solvent, under an inert atmosphere such as nitrogen or argon atmosphere in the presence of a strong base such as sodium hydride or lithium hydride, preferably sodium hydride. The reaction temperature is preferably from 0xc2x0 C. to boiling temperature of the reaction mixture, preferably at a reaction temperature between 10xc2x0 C. and about 150xc2x0 C.
Appropriate solvents for the reaction are dry polar aprotic solvents such as THF, dimethylsulfoxide (DMSO), dimethylacetamide or N,N-dimethylformamide (DMF), preferably DMF.
In the seventh step of the reaction, the oxo group of compound of formula V is reduced to obtain the corresponding hydroxy compound of formula Ia. The reaction is carried out under the same conditions described for reaction scheme 1 (step 4).
In the eighth step the methyl hydroxy group of compound of formula Ia is further reduced to the corresponding methylene group to obtain the compound of formula Ib. The reaction is carried out under the same conditions described for reaction scheme 1 (step 5).
The synthesis of compounds of formula I wherein R1 is acyl, C1-4-alkylsulfonyl or optionally substituted phenylsulfonyl, R2, R3 and X are as defined for compounds of formula I and R5 is aryl or heterocyclyl is preferably carried out in that compounds of formula XIII are acylated or sulphonylated to the corresponding compounds of formula I wherein R1 is acyl, C1-4-alkylsulfonyl or optionally substituted phenylsulfonyl. The acylation or sulphonylation reaction are known from textbooks about organic chemistry e.g. from J. March (1992), xe2x80x9cAdvanced Organic Chemistry:
Reactions, Mechanisms, and Structurexe2x80x9d, 4th ed. John Wiley and Sons). The further reaction steps are carried out in accordance with the reaction as described in reaction scheme 3.
As mentioned above, the compounds of formula I and hydrolyzable esters or ethers thereof or a pharmaceutically acceptable salt thereof are inhibitors of the human immunodeficiency virus reverse transcriptase enzyme both in vitro and in vivo, and can be used in the control or prevention of diseases mediated by the human immunodeficiency virus (HIV).
The activity of the compounds of formula I for the treatment of diseases mediated by the human immunodeficiency virus (HIV) can be demonstrated with the following assay methods.
Assay Method: HIV-1 Reverse Transcriptase Assay: Inhibitor IC50 Determination:
HIV-1 RT assay was carried out in 96-well Millipore filtermat NOB50 plates using purified recombinant enzyme and a poly(rA)/oligo(dT)16 template-primer in a total volume of 50 xcexcL. The assay constituents were 50 mM Tris/HCl, 50 mM NaCl, 1 mM EDTA, 6 mM MgCl2, 5 xcexcM dTTP, 0.1 xcexcCi [3H] dTTP, 5 xcexcg/ml poly (rA) pre annealed to 2.5 xcexcg/ml oligo (dT)16 and a range of inhibitor concentrations in a final concentration of 10% DMSO. Reactions were initiated by adding 5 nM HIV-1 RT and after incubation at 37xc2x0 C. for 30 min, they were stopped by the addition of 50 xcexcl ice cold 20%TCA and allowed to precipitate at 4xc2x0 C. for 30 min. The precipitates were collected by applying vacuum to the plate and sequentially washing with 2xc3x97200 xcexcl of 10% TCA and 2xc3x97200 xcexcl 70% ethanol. Finally the plates were dried and radioactivity counted in a Wallac Microbeta 1450 after the addition of 15 xcexcl scintillation fluid per well. IC50""s were calculated by plotting % inhibition versus log10 inhibitor concentrations.
Antiviral Assay Method:
Anti-HIV antiviral activity was assessed using an adaptation of the method of Pauwels et al. {Pauwels et al., 1988, J Virol Methods 20:309-321}. The method is based on the ability of compounds to protect HIV-infected T lymphoblastoid cells (MT4 cells) from cell-death mediated by the infection. The endpoint of the assay was calculated as the concentration of compound at which the cell viability of the culture was preserved by 50% (xe2x80x9850% inhibitory concentrationxe2x80x99, IC50). The cell viability of a culture was determined by the uptake of soluble, yellow 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and its reduction to a purple insoluble formazan salt. After solubilization, spectrophotometric methods were employed to measure the amount of formazan product.
MT4 cells were prepared to be in logarithmic-phase growth and a total of 2xc3x97106 cells infected with the HXB2-strain of HIV at a multiplicity of 0.0001 infectious units of virus per cell in a total volume of between 200-500 microliters. The cells were incubated with virus for one hour at 37xc2x0 C. before removal of virus. The cells are then washed in 0.01 M phosphate buffered saline, pH 7.2 before being resuspensed in culture medium for incubation in culture with serial dilutions of test compound. The culture medium used was RPMI 1640 without phenol red, supplemented with penicillin, streptomycin, L-glutamine and 10% fetal calf serum (GM10).
Test compounds were prepared as 2 mM solutions in dimethyl sulphoxide (DMSO). Four replicate, serial 2-fold dilutions in GM10 were then prepared and 50 microliters amounts placed in 96-well plates over a final nanomolar concentration range of 625-1.22. Fifty microliters GM10 and 3.5xc3x97104 infected cells were then added to each well. Control cultures containing no cells (blank), uninfected cells (100% viability; 4 replicates) and infected cells without compound (total virus-mediated cell death; 4 replicates) were also prepared. The cultures were then incubated at 37xc2x0 C. in a humidified atmosphere of 5% CO2 in air for 5 days.
A fresh solution of 5 mg/mL MTT was prepared in 0.01 M phosphate buffered saline, pH 7.2 and 20 microliters added to each culture. The cultures were further incubated as before for 2 hours. They were then mixed by pipetting up and down and 170 microliters of Triton X-100 in acidified isopropanol (10% v/v Triton X-100 in 1:250 mixture of concentrated HCl in isopropanol). When the formazan deposit was fully solubilized by further mixing, the absorbance (OD) of the cultures was measured at 540 nm and 690 nm wavelength (690 nm readings were used as blanks for artefacts between wells). The percent protection for each treated culture was then calculated from the equation:       %    ⁢          xe2x80x83        ⁢    Protection    =                                                                        (                                  OD                  ⁢                                      xe2x80x83                                    ⁢                  drug                  ⁢                                      -                                    ⁢                  treated                  ⁢                                      xe2x80x83                                    ⁢                  cultures                                )                            -                                                                          (                              OD                ⁢                                  xe2x80x83                                ⁢                untreated                ⁢                                  xe2x80x83                                ⁢                virus                ⁢                                  xe2x80x83                                ⁢                control                ⁢                                  xe2x80x83                                ⁢                cultures                            )                                                                                                      (                OD                 uninfected cultures)                            -                                                                          (                              OD                ⁢                                  xe2x80x83                                ⁢                untreated                ⁢                                  xe2x80x83                                ⁢                virus                ⁢                                  xe2x80x83                                ⁢                control                ⁢                                  xe2x80x83                                ⁢                cultures                            )                                            xc3x97    100    ⁢    %  
The IC50 can be obtained from graph plots of percent protection versus log10 drug concentration.
In both assays, compounds of formulas I range in activity from an IC50 of about 0.5 to about 10000 nM or 0.5 to about 5000 nM, with preferred compounds having a range of activity from about 0.5 to about 750 nM, more preferably about 0.5 to 300 nM, and most preferably about 0.5 to 50 nM.
The pyrazole derivatives provided by the present invention are useful in therapeutic treatment of the human or animal body, they are especially useful as inhibitors of the human immunodeficiency virus reverse transcriptase enzyme. Accordingly, the present pyrazole derivatives are therapeutically active substances in the treatment of diseases mediated by the human immunodeficiency virus (HIV) and can be used as medicaments for the treatment of such diseases.
They can be used as medicaments, especially for treating viral diseases, immune mediated conditions or diseases, bacterial diseases, parasitic diseases, inflammatory diseases, hyperproliferative vascular diseases, tumors, and cancer.
In particular, compounds of the present invention and pharmaceutical compositions containing the same are useful as chemotherapeutic agents, inhibitors of viral replication and modulators of the immune system, and can be used for the treatment of diseases mediated by the human immunodeficiency virus (HIV) other viral diseases such as retroviral infections (either alone or in combination with other antiviral agents such as interferon or derivatives thereof, such as conjugates with polyethylene glycol).
They can be used alone, or in combination with other therapeutically active agents, for example, an immunosuppressant, a chemotherapeutic agent, an anti-viral agent, an antibiotic, an anti-parasitic agent, an anti-inflammatory agent, an anti-fingal agent and/or an anti-vascular hyperproliferation agent.
The products in accordance with the invention can be used as medicaments, e.g. in the form of pharmaceutical preparations which contain them or their salts in admixture with a pharmaceutical, organic or inorganic carrier material which is suitable for parenteral or enteral administration, such as e.g. water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, Vaseline, etc. The pharmaceutical preparations can be present in solid form, e.g. as tablets, dragees, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. They may be sterilized and/or may contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure, anaesthetics or buffers. The compounds of formula I and their salts preferably come into consideration for oral administration and for this purpose are accordingly formulated.
The amount of the compound of formula I required for the treatment of viral diseases, especially diseases mediated by the human immunodeficiency virus (HIV) or other viral diseases will depend on a number of factors including the severity of the disease and the identity, sex and weight of the recipient and will ultimately be at the discretion of the attendant physician. In general, however, a suitable effective dose is in the range of 0.1 to 100 mg per kilogram of body weight of the recipient per day, preferably in the range 0.5 to 50 mg per kilogram of body weight per day and most preferably in the range of 1.0 to 30 mg of body weight per day. An optimum dose is about 5 to 25 mg per kilogram body weight per day. The desired dose is preferably presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day, preferably one, two, three, four or five sub-doses and most preferably one, two or three sub-doses. These sub-doses may be administered in unit dosage forms, for example, containing from 1 to 1500 mg, preferably from 100 to 1400 mg, most preferably from 400 to 1000 mg of active ingredient per unit dosage form.
The dosage of the compounds of general formula I and of the pharmaceutically compatible salts thereof with bases can vary within wide limits and in each individual case will, of course, be fitted to the individual requirements and to the pathogen to be controlled.
As mentioned earlier, medicaments containing a compound of general formula I or a pharmaceutically compatible salt thereof are likewise an object of the present invention, furthermore also a process for the production of such medicaments, which is characterized by bringing one or more compounds of general formula I or pharmaceutically compatible salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form.
It is preferable to administer the compound of formula I as a pharmaceutical formulation. The formulations of the present invention comprise at least one active ingredient of formula I together with one or more pharmaceutically acceptable exipients and optionally one or more other therapeutic agents. Formulations for oral administration may be capsules, cachets or tablets each containing a predetermined amount of active ingredient(s) may be prepared by any method well known in the art of pharmacy. As well as the active ingredients(s) the oral formulation may contain a binder (for example povidone, gelatin, hydroxypropylmethyl cellulose), a lubricant, inert diluent, preservative, disintegrant (for example sodium starch glycollate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) or a dispersing agent. Formulations for oral use may also include buffering agents to neutralise stomach acidity.
In the following examples the abbreviations used have the following significations:
All temperatures are given in degrees Celsius (xc2x0 C.).
The described NMR spectra were recorded on a Bruker DRX 400 MHz spectrometer with the probe temperature set at 300 K.
The mass spectra indicated by xe2x80x9c(M+; EI)xe2x80x9d, were recorded under electron impact conditions (EI), on a THERMOQUEST MAT95 S with a source temperature of 200xc2x0 C. Other mass spectra were recorded under electrospray ionization spectra (ESI) conditions, on one of the following machines:
THERMOQUEST SSQ 7000 [Solvent 0.085% TFA in 90% Acetonitrile/water; flow rate 100 microliters/minute; capillary 250xc2x0 C.; spray voltage 5KV; sheath gas 80 psi], or
LC-MS system (liquid chromatograph coupled to mass spectrum) THERMOQUEST TSQ 7000 ELECTROSPRAY or MICROMASS PLATFORM ELECTROSPRAY [Solvent 0.1% TFA in water or 0.085% TFA in 90% acetonitrile/water or 0.085% TFA in acetonitrile].
Compounds, whenever prepared by the processes of the present invention are also an object of the present invention.
The following examples illustrate the present invention: